OVERVIEW: What every practitioner needs to know

Are you sure your patient has viral myocarditis? What are the typical findings for this disease?

Myocarditis is inflammation of the heart muscle. Cardiomyopathy is dysfunction of the heart muscle with or without inflammation.

The most common identified cause of myocarditis in children is viruses. Viral myocarditis may present subacutely, with symptoms of congestive heart failure, or it may present acutely, with hypotension and cardiac failure. Myocarditis should be considered in the differential diagnosis of all children who present with unexplained congestive heart failure.

Symptoms of myocarditis in children:

Many patients have had a preceding flu-like or gastroenteritis-like illness. Most patients present with respiratory symptoms. Young infants may present with lethargy and poor feeding. Some children present with gastrointestinal symptoms— vomiting and abdominal pain. Patients may complain of palpitations or chest pain.

Myocarditis is an important cause of sudden death in previously healthy adolescents.

What other disease/condition shares some of these symptoms?

When respiratory symptoms are prominent, myocarditis may be misdiagnosed as pneumonia, bronchiolitis, or asthma.

Myocarditis may present like congestive heart failure due to other causes— including congenital malformations of the heart, valvular disease, cardiac ischemia, and Kawasaki disease. Patients with a slow onset of congestive failure and ventricular dilatation, without a viral prodrome, or with no evidence of inflammation, are often diagnosed with idiopathic dilated cardiomyopathy, rather than viral myocarditis. However, viral myocarditis may progress to chronic dilated cardiomyopathy, and it is difficult, on clinical grounds, to distinguish patients with myocarditis from those with dilated cardiomyopathy due to other causes.

Patients with severe myocarditis may appear "septic." Myocarditis should be suspected when shock is accompanied by cardiomegaly or pulmonary edema.

A number of metabolic and genetic diseases are associated with cardiomyopathy, and may cause similar signs and symptoms of myocardial dysfunction. These include endocrine disorders, connective tissue diseases, infiltrative diseases, drug reactions, nutritional deficiency, and familial storage diseases.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The chest X-ray most often shows an enlarged heart, pulmonary venous congestion, and/or pleural effusions. However, a normal X-ray is seen in rapidly progressing acute disease.

The electrocardiogram shows sinus tachycardia, low voltages in the precordial leads, and ST-T wave abnormalities. Arrhythmias and conduction defects may be observed.

The echocardiogram typically shows left ventricular enlargement and decreased contractility. Similar findings may be observed in non-inflammatory cardiomyopathy

Magnetic resonance imaging (MRI) may be helpful in distinguishing inflammation from fibrosis or other pathologic processes.

Endomyocardial biopsy, demonstrating lymphocytic infiltration and myocyte necrosis, has been considered the definitive diagnostic test, but its clinical value is uncertain and it is no longer commonly performed. Because of sampling error, biopsy may be falsely negative, and the biopsy procedure is risky in severely ill infants. In most cases, the diagnosis can be established with noninvasive tests.

If you are able to confirm that the patient has viral myocarditis, what treatment should be initiated?

Children with myocarditis should be managed in a hospital where pediatric intensive care support is available. Children with fulminant disease— those with severe acute heart failure or cardiogenic shock— will require mechanical ventilation, inotropic support, and afterload reduction. In some cases, mechanical circulatory support— either extracorporeal membrane oxygenation (ECMO) or placement of a left ventricular assist device (LVAD)— will be necessary. Arrhythmias or heart block may necessitate additional interventions.

Children with milder congestive failure are monitored and managed with diuretics and angiotensin-converting enzyme (ACE) inhibitors; digoxin is commonly used for management of congestive failure, although has been reported to be deleterious in an animal model of myocarditis. The role of beta-blockers in treating heart failure in children is not certain, but they are known to be helpful in adults.

Bedrest is important for all children with acute myocarditis.

The pathogenesis of myocarditis is believed to involve direct viral damage to the myocardium, as well as damage caused by the inflammatory response to the virus and, perhaps, to cross-reactive cardiac antigens. This suggests a possible role for antiviral and immunomodulatory treatments. However, at this time, antiviral agents, interferon, and immunosuppressive agents (such as steroids, azathioprine, and cyclosporine) have not been shown to change the outcome of viral myocarditis or suspected viral myocarditis. In some less common forms of myocarditis— such as hypersensitivity or eosinophilic myocarditis— immunosuppression and steroids are effective.

Based on anecdotal experience, and an influential study involving only historical controls, a number of prominent pediatric hospitals use high dose intravenous immunoglobulin (IVIG) for treatment of myocarditis. There are no randomized placebo-controlled studies of IVIG in pediatric patients, and a randomized study in adults showed no beneficial effect. However, many pediatric cardiologists believe that, until definitive data are available, the risk-benefit ratio strongly favors the use of IVIG.

What are the adverse effects associated with each treatment option?

Although steroids and immunosuppressive drugs are used to treat myocarditis in many centers, they have the potential to interfere with the immune control of virus replication. Adverse reactions to IVIG are uncommon and usually transient (fever, chills, volume overload); nephrotoxicity, hemolysis, thromboembolic events, and aseptic meningitis have also been observed.

What are the possible outcomes of viral myocarditis?

The majority of children with viral myocarditis recover completely, and children with mild disease may never be diagnosed. In documented cases, there is 10% mortality overall; poor outcomes are associated with very poor left ventricular contractility at presentation.

Children with fulminant myocarditis— characterized by a short viral prodrome, acute onset of severe myocardial dysfunction, and normal heart size— do surprisingly well, given the severity of their illness. Even among those who require ECMO support, 80% survive without the need for heart transplantation.

The prognosis in idiopathic dilated cardiomyopathy is not as good: 20% of affected children die, and 40% go on to transplantation.

How to these pathogens/genes/exposures cause the disease?

Our understanding comes largely from studies of mice infected with coxsackievirus B. The outcome of infection depends on the properties of the virus, and the genetic background of the host. Some virus isolates cause myocarditis, whereas others infect without affecting the heart; some mouse strains develop acute disease, some develop chronic disease, and others appear resistant to myocarditis.

Coxsackievirus passes through the bloodstream to reach the heart, and replicates within cardiomyocytes; the virus causes direct damage to the cardiomyocytes (viral enzymes specifically cleave cellular proteins) and causes cell death by triggering apoptotic mechanisms.

Virus replication also stimulates the host's immune response, which ultimately limits virus replication, but may also cause further damage to the myocardium. Lymphocytes specifically recognize and kill virus-infected cells, which are incapable of regeneration; in some cases, an autoimmune response is triggered, in which lymphocytes and antibodies directly recognize myocardial antigens, causing damage even after the virus has been eliminated.

It is possible that cytokines released in response to virus infection suppress myocardial contractility, and thus contribute to the reversible cardiac dysfunction seen in some cases of acute myocarditis.

Virus genomes sometimes persist within the myocardium, even when production of infectious virus has ceased; these appear to contribute to further damage by unknown mechanisms. It is not clear what determines whether the myocardium recovers fully, or whether progressive dysfunction ensues.

The mechanisms by which other viruses cause myocardial damage are even less well understood.

Ongoing controversies regarding etiology, diagnosis, treatment

The precise role of endomyocardial biopsy is not certain in children with myocarditis. The value of IVIG, corticosteroids, and immunosuppressive drugs remains controversial.